Cancer Treatment: The Critical Factors
Step Four: Inhibiting the Cyclooxygenase Enzymes (COX-1 and COX-2)
Inflammation plays a pivotal role in the formation and progression of cancer. There are many inflammatory pathways in the body. The cyclooxygenase (COX-2) enzyme is a particular inflammatory pathway that has been the focus of research in the realm of oncology. Initially, scientists believed COX-2 was merely an inducible response to inflammation. It is now speculated that COX-2 performs biological functions in the body, particularly in the brain and kidneys as well as the immune system. COX-2 becomes troublesome when upregulated (sometimes 10- to 80-fold) by pro-inflammatory stimuli (interleukin-1, growth factors, tumor necrosis factor, and endotoxins). When overexpressed, COX-2 participates in various pathways that could promote cancer (ie, angiogenesis), cell proliferation, and the production of inflammatory prostaglandins.28-30
A growing body of research has documented the relationship between COX-2 and cancer:
- An article in the journal Cancer Research showed that COX-2 levels in pancreatic cancer cells are 60 times greater than in adjacent normal tissue.31
- Solid tumors contain oxygen-deficient or hypoxic areas (a reduced oxygen supply to a tissue below physiological levels). Hypoxia promotes up-regulation of COX-2 and angiogenesis, and establishes resistance to ionizing radiation.32
- Within the nonsteroidal anti-inflammatory drug (NSAIDs) class is a subclass referred to as COX-2 inhibitors (cyclooxygenase inhibitors). COX-2 inhibitors were popularly prescribed to relieve pain but now have found a place in oncology. It began when scientists recognized that people who regularly take NSAIDs lowered their risk of colon cancer by as much as 50%.33
- JAMA reported that a 9.4-year epidemiological study showed that COX-2 upregulation was related to more advanced tumor stage, tumor size, and lymph node metastasis as well as diminished survival rates among colorectal cancer patients.34 With more regular use of aspirin (a COX-2 inhibitor), the risk of dying from the disease decreased.35,36 The journal Gastroenterology reported additional encouragement, showing that three different colon cell lines underwent apoptosis (cell death) when deprived of COX-2; when lovastatin was added to the COX-2 inhibitor the kill rate increased another five-fold.37 The benefits observed with COX-2 inhibitors extend beyond colon protection to the cardiovascular system, where they help sustain endothelial cell function.38
- A groundbreaking study published in 2009 revealed that breast cancer patients treated with COX-2 inhibitors had a greatly reduced risk of bone metastases. In this investigation, the incidence of bone metastases were recorded in breast cancer patients not treated with a COX-2 inhibitor, as well as in individuals who received a COX-2 inhibitor for at least six months following the diagnosis of breast cancer. The findings were astounding—those who were treated with a COX-2 inhibitor were 90% less likely to develop bone metastases than those who were not treated with a COX-2 inhibitor.39
- 134 patients with advanced lung cancer were treated with chemotherapy alone or combined with Celebrex (a COX-2 inhibitor). For those patients with cancers expressing increased amounts of COX-2, treatment with Celebrex dramatically prolonged survival.40
- Celebrex slowed cancer progression in men with recurrent prostate cancer.41,42
- Celebrex prevented weight loss and improved quality of life in individuals with head and neck cancers.43
- Regular intake of over-the-counter (OTC) NSAIDs produced highly significant composite risk reductions of 43% for colon cancer, 25% for breast cancer, 28% for lung cancer, and 27% for prostate cancer. Furthermore, in a series of case control studies, daily use of a selective COX-2 inhibitor, either celecoxib or rofecoxib, significantly reduced the risk for each of these malignancies. The evidence is compelling that anti-inflammatory agents with selective or non-selective activity against cycloooxygenase-2 (COX-2) have strong potential for the chemoprevention of cancers of the colon, breast, prostate and lung. Results confirming that COX-2 blockade is effective for cancer prevention have been tempered by observations that some selective COX-2 inhibitors pose a risk to the cardiovascular system.44
Life Extension recognizes the value of COX-2 inhibitors in cancer treatment. Some progressive oncologists include COX-2 inhibitors in their anticancer protocols, but the numbers are still relatively few. The risks associated with traditional NSAIDs include gastrointestinal perforation, ulceration and bleeding, and less frequently, renal and liver damage, but the benefits of for certain cancer patients may outweigh these risks.
A number of natural COX-2 inhibitors are discussed in the protocol entitled “Cancer Adjuvant Therapy.”
Like COX-2, the COX-1 enzyme also catalyzes (mediates) the conversion of certain fatty acids into inflammatory end products in some cell types. Cancer cells are sometimes genetically altered in such a way that causes them to express higher levels of COX-1; this has been observed in several types of cancer including ovarian, colon, and head and neck cancers.45-47 Moreover, selectively inhibiting COX-1 with experimental compounds has demonstrated a marked reduction in viability of colon cancer cells and ovarian cancer cells.47,48
Experimental studies on breast cancer cells revealed that simultaneous inhibition of both COX-1 and COX-2 might exert a synergistic effect to combat cancer cell growth.49 The authors of this study concluded that "The significant and additive effects exhibited by the combination of COX-1 and -2 inhibitors and their effects on cell cycle suggest that these agents could become an effective treatment modality for carcinoma of the breast."
Aspirin is an NSAID, but its actions are unique in that it selectively inhibits COX-1 activity while modulating the expression of COX-2.50 The net result of this dualistic action is diminished production of harmful metabolites via COX-1 and a reduction in total COX-2 activity. Since both COX-1 and COX-2 are drivers of inflammatory cancer cell growth, aspirin is an important yet underappreciated anticancer drug.
At the forefront of the growing field of research into aspirin’s role as a cancer fighter is Professor Peter Rothwell of Oxford University. Having specialized primarily in cardiovascular medical research, he and his colleagues had at their disposal a trove of information compiled from eight massive studies examining the effect of aspirin therapy on cardiovascular health.
Among the most compelling of their findings:
- Aspirin reduced the overall risk of death from cancer by approximately 20%.
- Most of that benefit was due to a 30‒40% reduction in deaths occurring after five years of daily aspirin intake.
- The reduction in deaths due to solid cancers was maintained for 20 years in studies in which data was available for that period of time.
- These effects were consistent across all populations studied—despite their diversity in health histories.
- A dose of just 75 mg daily was all that was required for the protective effect—higher doses did not increase the benefit.
- The reduction in cancer deaths increased with age: peak effects were observed in people aged 55‒64 and remained high in those 65 years or older.
- The effect of aspirin on reducing risk of fatal cancers was powerful enough to contribute to a significant reduction in mortality rates from all causes.
The data correlating aspirin therapy with colon cancer prevention proved particularly compelling. Rothwell’s team saw a 24% reduction in the risk of developing colon cancer over a 20-year period in patients who took aspirin daily and a 35% reduction in the risk of dying from colon cancer. The most potent preventive benefit was observed in cancers of the upper colon (the ascending and transverse colon).51
Separate observational studies have suggested a preventive effect for cancers of the esophagus, stomach, lung, breast, and ovaries.52-54 A 2010 study revealed that men taking regular aspirin supplements attained a 10% reduction in prostate cancer risk compared to men who took no aspirin.55 Another study showed a risk reduction of 24% in long-term users (greater than five years), and 29% in daily aspirin users.56
How to Implement Step Four
- Take a low-dose aspirin each day, and;
- Ask your physician to prescribe one of the following COX-2 inhibiting drugs:
- Lodine XL, 1000 mg once daily, or
- Celebrex, 100‒200 mg every 12 hours
Note: The use of Lodine and Celebrex has been associated with an increased risk of heart attack and stroke. The anti-cancer benefits of these drugs have to be weighed against these increased cardiovascular risks. Using aspirin in combination with a COX-2 inhibitor may increase the risk for bleeding, but also reduce cardiovascular risks; speak with your physician before combining aspirin with a COX-2 inhibitor.